J. Wharton et al., Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells, CIRCULATION, 102(25), 2000, pp. 3130-3136
Citations number
32
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Prostacyclin has proved to be a beneficial treatment for patient
s with severe pulmonary hypertension. We postulated that the response may r
eflect, at least in part, inhibition of pulmonary artery smooth muscle cell
(PASMC) growth.
Methods and Results-Human PASMCs were derived from distal (<1-mm external d
iameter, n=8) and proximal (>8-mm external diameter, n=12) pulmonary arteri
es obtained at transplant surgery and pneumonectomy. The effects of the sta
ble prostacyclin analogues on [methyl-H-3]thymidine incorporation and cell
proliferation were investigated by using immunohistochemically characterize
d cells. Distal cells proliferated faster than did proximal PASMCs and disp
layed a distinct sensitivity to cicaprost and iloprost. Both analogues inhi
bited thymidine uptake over 24 hours (20% to 60%, P<0.001; n=8) and abolish
ed stimulation of DNA synthesis by platelet-derived growth factor-BB (10 ng
/mL) in distal but not proximal cells. The inhibitory effect of cicaprost w
as mimicked by isoproterenol (10(-5) mol/L), forskolin (10(-5) mol/L), and
dibutyryl cAMP (5x10(-4) mol/L) and was potentiated by the phosphodiesteras
e inhibitor 3-isobutyl-1-methylxanthine (5 x 10(-5) mol/L). Cicaprost (10(-
10) to 10(-6) mol/L) inhibited the proliferation of PASMCs, which had been
stimulated with either platelet-derived growth factor-BB or serum, and incr
eased cAMP production. These effects were potentiated by 3-isobutyl-1-methy
lxanthine and attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyade
nosine (10(-5) to 10(-4) mol/L).
Conclusions-Cicaprost and iloprost inhibit DNA synthesis and proliferation
to a greater extent in distal compared with proximal human PASMCs, acting a
t least in part via a cAMP-dependent mechanism. The results are consistent
with the hypothesis that prostacyclin analogues inhibit vascular remodeling
in pulmonary hypertension and demonstrate heterogeneity among human PASMCs
.